Drug abuse is a major problem for both the medical and legal systems because of the ability of illicit drugs to undesirably alter human behavior. Cyclic AMP-mediated signaling in the region of the striatum known as the nucleus accumbens (NAc) is critically involved in behavior modifications caused by drugs of abuse. However, the role of CAMP signaling in the synaptic properties of the NAc, and the role of these synaptic properties in drug addictive behaviors are poorly understood. In this proposal, I will outline a multidisciplinary approach designed to examine the correlation between cAMP signaling, synaptic plasticity in the NAc, and behavioral paradigms dependent on the NAc and related to drug addictive states. I will take advantage of a transgenic mouse line which inducibly overexpresses an activated form of the catalytic subunit of camp-dependent protein kinase (PKA) (tTA-C(QR) mice), to examine the function of this protein in the biochemistry, electrophysiology and behavior of the mouse in paradigms related to drug addiction. The specific aims of this proposal are first, to determine the role of the cAMP/PKA cascade in synaptic plasticity at glutamatergic synapses in the mouse NAc, using slice electrophysiological techniques and pharmacologic and genetic manipulations of the cAMP/PKA cascade. Next, I will determine whether postsynaptic PKA substrate phosphorylation is correlated with CAMP cascade-mediated changes in synaptic transmission. This will be done using Western blot technology with phospho-specific antibodies to known postsynaptic PKA substrates. Finally, I will examine the effects of PKA transgene induction on Nac-dependent, addiction-related behavioral models, namely conditioned place preference and response reinforcement learning.